Clopidogrel bisulfate (currently sold under the brand name Plavix; clopidogrel bisulfate will occasionally be referred to herein simply as “clopidogrel”) is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically, it is referred to as methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-acetate sulfate (1:1) and is a prodrug. Clopidogrel is available as a 75 mg or 300 mg tablet.
Clopidogrel is an antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease and cerebrovascular disease. Specifically, clopidogrel is indicated for acute coronary syndrome (“ACS”): (1) for patients with non-ST-segment elevation ACS; (2) for patients with ST-elevation myocardial infarction; and (3) recent myocardial infarction, recent stroke, or established peripheral arterial disease. Clopidogrel is also used, along with aspirin, for the prevention of thrombosis after placement of intracoronary stent or as an alternative antiplatelet drug for patients who are intolerant to aspirin.
Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. Many PPIs are benzimidazole derivatives (specifically, substituted benzimidazole derivatives). Examples of some of the most common PPIs include:
Omeprazole (currently sold under the brand names: Losec, Prilosec, Zegerid, Lomac, Omepral, Omez);
Lansoprazole (currently sold under the brand names: Prevacid, Zoton, Inhibitol, Levant, Lupizole);
Dexlansoprazole (currently sold under the brand name: Dexilant);
Esomeprazole (currently sold under the brand names: Nexium, Esotrex); and
Pantoprazole (currently sold under the brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Zentro, Pan)
The PPIs in the above list are substituted benzimidazoles that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system of the secretory surface of the gastric parietal cell.
Proton pump inhibitors are often prescribed with clopidogrel to reduce the risk of gastric bleeding or hemorrhage associated with the anti-platelet effect of clopidogrel therapy. There is significant ongoing concern regarding the clinical outcomes of patients taking clopidogrel and PPIs. Recently published studies suggested that PPIs have the potential to reduce the clopidogrel, G-protein coupled, 12 (P2Y12) adenosine diphosphate (ADP) receptor (Gilard M, Arnaud B, Cornily J C, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51(3):256-60; Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008; 52(12): 1038-39; Ho P, Maddox T, Wang L, Fihn S, Jesse R, Peterson E, et al. Proton pump inhibitors may attentuate the benefits of clopidogrel among ACS patients: empirical evidence from 3,311 ACS patients. Circulation 2008; 118:S_1165. Abstract No. 6241; Aubert R, Epstein R, Teagarden J, Xia F, Yao J, Desta Z, et al. Proton pump inhibitors effect on clopidogrel effectiveness: the clopidogrel Medco outcomes study. Circulation 2008; 118:S_815. Abstract 3998).
Clopidogrel itself does not possess antiplatelet aggregation activity, but requires metabolism by hepatic cytochrome P450s, including CYP2C19, to an active metabolite that then blocks platelet P2Y12 receptors. Because PPIs are known inhibitors of CYP2C19, a plausible explanation for this reduced effectiveness of clopidogrel may be a metabolism-based drug-drug interaction (DDI) whereby the PPI inhibits the conversion of clopidogrel to its active metabolite by inhibiting CYP2C19. The FDA has made warnings about clinically relevant DDI with respect to clopidogrel and certain PPIs. For example, on Nov. 17, 2009, the FDA posted the following warning about a drug interaction between clopidogrel and omeprazole:                “FDA notified healthcare professionals of new safety information concerning an interaction between clopidogrel (Plavix), an anti-clotting medication, and omeprazole (Prilosec/Prilosec OTC), a proton pump inhibitor (PPI) used to reduce stomach acid. New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.        Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.”        
Angiolillo et al. in Clin. Pharmacology & Therapeutics, pages 1-10 (Sep. 15, 2010), report the results of a series of four metabolic DDI studies using omeprazole, pantoprazole and clopidogrel conducted in healthy subjects. Specifically, study 1 administered a 300-mg loading dose and 75 mg/day maintenance dose of clopidogrel and omeprazole (80 mg) simultaneously to the healthy patients. Study 2 administered the clopidogrel and omeprazole of study 1 twelve (12) hours apart to the healthy patients. In study 3, the amount of clopidogrel from study 1 was increased to 600-mg loading/150 mg/day maintenance dose. Study 4 administered a 300-mg loading dose and 75 mg/day maintenance dose of clopidogrel and pantoprazole (80 mg) simultaneously to the healthy patients. The results showed that a metabolic DDI was found to exist between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.
However, since not all PPIs inhibit CYP2C19 to the same extent, the potential for a clinically relevant DDI with clopidogrel may not be generalized to all PPIs. Thus, there is a need in the art for new methods of treating patients suffering from heartburn who are concomitantly being administered clopidogrel to treat a second disease state or to prevent of gastric bleeding or hemorrhage in patients being treated with clopidogrel.